Updated October 17, 2018
Over the last decade, scientists have discovered many genes related to ALS, but there are still many questions about how mutations in those genes spark the development of the disease. The range of onset for ALS is wide: it can occur anytime in adulthood. The disease duration is usually two to five years after diagnosis but can range from six months to more than 20 years. Why does the disease manifest so differently among those who develop it — even among those who have the same ALS-related gene mutations?
Dr. Ekaterina Rogaeva is a geneticist at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto. For the past 25 years, she has been researching genetics for different forms of movement disorders and dementia, with a focus on ALS, Parkinson’s disease, Alzheimer’s disease and frontotemporal dementia.
Together with Dr. Lorne Zinman at the Sunnybrook Research Institute’s ALS Clinic, Dr. Rogaeva has observed that ALS disease onset and progression can be very different in identical twins. For example, in one set of identical twins with a C9orf72 gene mutation, one twin had been living with slowly-progressing ALS for 17 years, while the other twin had no ALS symptoms. Their finding is surprising because identical twins have the exact same genetic makeup.
“This discovery made me wonder what else influences age of onset and how ALS develops,” says Dr. Rogaeva. “There must be other factors apart from the genetics.”
Environmental factors, like exposure to smoking, for example, can leave marks on our DNA, turning genes
“off” without changing the underlying sequence of the DNA. This marking process is called DNA methylation. With today’s advanced technology, scientists can see the locations where DNA methylation occurs in DNA from blood samples.
“Measuring the accumulation of marks on genes over time, called DNA methylation age, may be the most accurate way to measure biological age,” says Dr. Rogaeva.
Since the strongest risk factor for ALS is aging, she has been investigating whether differences in DNA methylation age can provide new insights into why ALS begins and progresses differently. In her recent research, Dr. Rogaeva and colleagues examined DNA methylation in blood samples from people with C9orf72-related ALS and found that acceleration of aging is linked to a shorter disease duration and earlier age of onset.
On Wednesday, October 17, 2018, Dr. Rogaeva spoke at the ALS Canada 2018 Virtual Research Forum where she talked about her quest to understand whether genetic and environmental influences can explain why ALS affects people so differently and what that means for the next steps in her research.